Chemical Volume 8 Number 1 January 2017 Pages 1–810 Science rsc.li/chemical-science ISSN 2041-6539 EDGE ARTICLE Naoya Kumagai, Masakatsu Shibasaki et al. Pyramidalization/twisting of the amide functional group via remote steric congestion triggered by metal coordination Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Pyramidalization/twisting of the amide functional group via remote steric congestion triggered by Cite this: Chem. Sci.,2017,8,85 metal coordination† Shinya Adachi, Naoya Kumagai* and Masakatsu Shibasaki* For decades, the planarity of the amide functional group has garnered sustained interest in organic chemistry, enticing chemists to deform its usually characteristic high-fidelity plane. As opposed to the construction of amides that are distorted by imposing rigid covalent bond assemblies, we demonstrate herein the deformation of the amide plane through increased steric bulk in the periphery of the amide moiety, which is induced by coordination to metal cations. A crystallographic analysis revealed that the thus obtained amides exhibit significant pyramidalization and twisting upon coordination to the metals, Received 16th August 2016 while the amide functional group remained intact. The observed deformation, which should be Accepted 21st September 2016 attributed to through-space interactions, substantially enhanced the solvolytic cleavage of the amide, DOI: 10.1039/c6sc03669d Creative Commons Attribution 3.0 Unported Licence. providing compelling evidence that temporary crowding in the periphery of the amide functional group www.rsc.org/chemicalscience may be used to control the reactivity of amides. Introduction of B, which lacks an amide resonance, and exhibits a remark- ably short half-life of <15 s in water.5d Besides these extreme s c The amide bond is characterized by its thermodynamic stability examples, a number of amides that exhibit unusual and N and kinetic tolerance toward hydrolytic cleavage, which arises values have been reported, typically using covalently distorted 1,7,8 from conjugation via the planar O–C–N array.1 Under neutral bridged lactam architectures. These structurally intriguing This article is licensed under a conditions in aqueous solution at ambient temperature, non- bonds may not only be of fundamental academic interest, but activated amide bonds have a half-life of ca. 100 years.2 This also of signicant applied importance in life science, consid- high stability is usually attributed to the resonance interaction ering that amides constitute the primary backbone of proteins. p* ffi between the nN and C]O orbitals, which occurs most e - Open Access Article. Published on 23 September 2016. Downloaded 9/25/2021 1:10:25 AM. ciently in a planar geometry with a shortened and stronger C–N bond. Therefore, amide bonds are commonly used as a robust structural motif (e.g. in synthetic polymers), and the hydrolysis of the amide bond in a practical timescale requires general harsh conditions (e.g. high or low pH at elevated temperatures). The deformation of the co-planarity of the amide bond repre- sents an intuitive strategy to lower its robustness, which was initially proposed by Lukeˇs in 1938, who presented a model of strained “twisted amides” with a nitrogen atom at the bridge- head position.3 The longstanding pursuit toward twisted amides led to the identication of extreme examples of fully- characterized and highly distorted amides (A–C),4,5 which exhibited twist angles (s) and pyramidalization (cN) values at the nitrogen, dened by Winkler and Dunitz,6 of ca. 90 and 60, respectively (Fig. 1a). The prime importance of the resonance interaction for stabilizing the amide bond manifests in the case Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo Fig. 1 (a) Extreme examples of highly distorted amides in a covalent 141-0021, Japan. E-mail: [email protected]; [email protected] framework, (b) deformation/activation of amides via the coordination † Electronic supplementary information (ESI) available. CCDC 1494998–1495005. of the amide nitrogen to metals, and (c) the distortion of the amide For ESI and crystallographic data in CIF or other electronic format see DOI: induced by peripheral steric constraints upon the coordination to 10.1039/c6sc03669d metal cations. This journal is © The Royal Society of Chemistry 2017 Chem. Sci.,2017,8,85–90 | 85 View Article Online Chemical Science Edge Article Indeed, the involvement of distorted amides has been invoked both the bulky benzophenone imine and the R2 group on the for enzymatic transformations.1,9 In this context, we were inter- pyridine ring to swing close to the amide, thus compromising ested in distorting the amide planarity using an external trigger; the amide planarity via through-space steric bias (Fig. 2a, II). more specically, instead of constructing covalently assembled With this blueprint in hand, we set out to synthesize three distorted amides, we aimed at inducing the amide deformation derivatives, which contain R2 groups of varying steric bulk: H via temporary non-covalent interactions. Although several (1a), Me (1b), and 2,6-dimethylphenyl (1c) (Fig. 2b).13 While 1b reports link the deformation and activation (e.g. hydrolysis and and 1c were synthesized as (E)-crotonyl amides, 1a was based on E/Z isomerization) of amides to the coordination of the amide a p-uorocinnamoyl amide in order to increase its crystallinity. nitrogen to metal cations (Fig. 1b),10,11 substantial amide defor- The coordination of 1a to azophilic Pd2+ cations, which favor mation without direct coordination of the amide nitrogen or a square-planar coordination mode, afforded in aprotic solvents oxygen has, to the best of our knowledge, not yet been reported. the corresponding complexes. The formation of these Herein, we show that it is possible to induce signicant pyr- complexes, which are thermodynamically stable under anhy- amidalization and twisting of the amide functional group by drous conditions at ambient temperature, was monitored using remote steric congestion upon the coordination of the substit- 1H and 13C NMR spectroscopy. The NMR analysis revealed that uents attached to the amide nitrogen to a metal cation (Fig. 1c). A 1a/Pd (1a :Pd¼ 1 : 1) and (1a)2/Pd (1a :Pd¼ 2 : 1) complexes crystallographic analysis revealed that the substantial deforma- were formed depending on the ratio of 1a and [Pd(CH3CN)4]- tion of the amide planarity occurs without direct coordination of (BF4)2 (Fig. 3). In CD3CN, a 1 : 1 mixture of 1a and [Pd(CH3- 1a the amide. Peripheral crowding being a viable strategy to weaken CN)4(BF4)2 favored the formation of /Pd. The observed NOE the amide linkage is supported by the observed rapid solvolysis signals between He and Hd are consistent with the anticipated 12 of the thus obtained distorted amides. coordination mode via Npy and NIm, in which the amide 14 nitrogen NAm is le uncoordinated (Fig. 3a and b). The char- acteristic downeld shi of the b-olenic proton Hf upon Results and discussion ] Creative Commons Attribution 3.0 Unported Licence. complexation implied an increased polarization of the C O We began our study by designing a suitable amide with metal- bond via distortion of the amide moiety. The formation of the 1a coordination sites that may be able to create a steric bias upon homoleptic complex ( )2/Pd from bidentate coordination via 1 13 the addition of appropriate metal cations. As the metal coor- Npy and NIm induced similar spectral changes in the H and C dination should be orthogonal to the amide functional group, NMR spectra, together with diagnostic NOE signals between the 1a 1a we selected a combination of azophilic metals and nitrogen- two fragments (Ha and Hi; Fig. 3c). For ( )2/Pd, the observed based bidentate coordination sites. Fig. 2a shows the generic down eld shi of Hf was even more pronounced, which was structure of amide 1 with a 3-substituted-2-hydrazonopyridine tentatively ascribed to the deshielding effect of the phenyl group 1a moiety, which contains an amide (NAm) and an adjacent imine on the opposite /Pd fragment (Fig. 3b and c and 4d; vide This article is licensed under a 13 (hydrazone of benzophenone; NIm) functional group. It should infra). Unfortunately, the chemical shi s in the C NMR be noted that 1 prefers a planar amide structure, which is spectra were not straightforward to interpret (Fig. 3d–f); in achieved by tilting the pyridine ring and the imine along the contrast to the rather subtle changes to the resonances for the C(pyridine)–NAm and NAm–NIm single bonds, respectively amide carbonyl (CAm) moiety, the signal for the imino carbonyl Open Access Article. Published on 23 September 2016. Downloaded 9/25/2021 1:10:25 AM. (Fig. 2a, I). Conversely, we anticipated that the addition of (CIm) fragment experienced a substantial down eld shi . In the azophilic cations (M) should induce a bidentate chelation Ph group-rich environment of these complexes, the downeld ff through NIm and NPy, thus a ording a rigid and planar shi of the amide carbonyl via distortion and the imino 5-membered cycle. This conformational change should provoke carbonyl via direct coordination might be increased and decreased, respectively, by shielding and deshielding effects from nearby multiple bonds (vide infra). The distortion of the amide plane in 1a by peripheral crowding was further examined via single-crystal X-ray diffrac- tion analysis (Fig. 4a and d). Single crystals of amide 1a and its Pd complex (1a)2/Pd were obtained from acetone/hexane, and their solid-state structures are shown in Fig. 4a and d, while selected bond lengths and distortion parameters are summa- rized in Table 1. In 1a, the pyridyl and the hydrazine group occupy the far side of the amide group in order to minimize steric repulsion. The amide group exhibited a negligible twist angle (s ¼ 3.0), whereas partial pyramidalization was observed c ¼ for the amide nitrogen ( N 19.6 ).